The retinoids are analogues of Vitamin A and have earned a prominent role in the treatment of dermatological disorders. However, the extent of their true potential may yet be realized in cancer chemoprevention and treatment. Consequently, structure-activity relationships have been studied in an attempt to uncouple the structural features which are responsible for pharmacological activity from those causing toxicity to the host. However, the in vivo activity of a given retinoid is not necessarily well-predicted by its in vitro pharmacological activity. The oral absorption is of particular concern since the structural modifications which enhanced pharmacological activity would be expected to lead to a decrease in aqueous solubility with a resultant decrease in bioavailability. However, bile salt micelle solubilization and transport is known to be important for the absorption of retinol. If better understood, this process could be exploited to achieve the oral delivery of insoluble drugs with high intrinsic pharmacological activity. The specific aims of this project are to study the influence of chemical structure on the initial steps in retinoid absorption by the intestine: solubilization of the retinoid by bile salt mixed micelles, transport through the aqueous boundary layer, and transfer of the retinoid from the mixed micelle to the brush border membrane of the enterocyte. To evaluate the influence of chemical structure on absorption of retinoids, two classes of retinoic acid analogues will be evaluated. The first class of molecules are all-trans-retinoic acid analogues with various functional groups in the hydrophilic portion of the molecule. These analogues will include: all-trans-retinoic acid, 13-cis-retinoic acid (isotretinoin), all-trans-retinoic acid ethyl ester, N- ethylretinamide, retinyl methyl ether, and N-(4-hydroxyphenyl)retinamide. The second class of retinoic acid analogues will contain sterically restricted conformations in the polyene chain. The structural rigidity of these compounds, known as arotinoids, would be hypothesized to influence the extent of solubilization in the mixed micelles that mediate the absorption of the retinoids from the intestinal lumen. To understand the structural requirements that determine the extent of absorption, the following specific studies will be carried out. the retinoid physicochemical properties relevant to intestinal absorption, including aqueous solubility, bulk phase partition coefficient, bile acid mixed micelle/aqueous distribution coefficient and the bile acid mixed micelle/phospholipid membrane vesicle transfer rate and distribution coefficient will be evaluated. These physicochemical properties will then be related to the absorption of the retinoids as determined in the in situ perfused rat intestinal lumen model. The ultimate goal of the work is the establishment of chemical design features which will maximize the oral bioavailability of the retinoids by improvement of absorption from the gastrointestinal lumen.